化疗药/抗癌蛋白共递送载体的制备及其在肿瘤协同治疗中的应用

Polymeric nanocarriers provide a promising strategy to efficiently deliver antitumor drugs for cancer therapy. However, co-encapsulation of hydrophobic chemotherapeutics and hydrophilic proteins has proven difficult due to their distinct physicochemical properties. Moreover, the polymeric nanocarriers are required to timely release the small drugs and therapeutic proteins after cellular internalization and mediate effective endolysosomal escape of the protein cargoes to fulfill their biological functions. To address these issues, a series of triblock copolymers comprising mPEG, catechol-containing block and tertiary amine-containing block will be synthesized in this proposal, and the phenylboronic acid-modified protein therapeutics will be loaded based on reversible phenylboronic acid-catechol interactions, meanwhile, hydrophobic drugs will be co-encapsulated by hydrophobic interactions between the drugs and hydrophobic tertiary amine-containing block under physiological conditions. After cellular internalization, protein therapeutics will be released from the nanoparticles in acidic endolysosomal environment due to the pH-responsiveness of phenylboronic acid-catechol interactions. The hydrophobic tertiary amine-containing block will become hydrophilic after tertiary amines are protonated in acidic pH, resulting in pH-responsive drug release. The protonation of tertiary amines will also induce proton sponge effect and will promote the endolysosomal escape of phenylboronic acid-modified proteins. Then the protein therapeutics will be reactivated by intracellular reactive oxygen species (ROS)-triggered phenylboronic acid-deprotections, and the released drugs and protein therapeutics are supposed to mediate synergistic anticancer effect.

高分子纳米载体的出现为抗肿瘤药物的高效递送提供了新的方法。然而，如何在同一个纳米结构中高效共担载理化性质极大不同的疏水化疗药物和亲水蛋白药物，实现两种药物在细胞内的可控释放，以及蛋白药物的内涵体/溶酶体逃逸是这两种药物共递送载体开发所面临的巨大挑战。为解决以上问题，本项目拟制备包含mPEG、含邻苯二酚侧基聚谷氨酸链段和含三级胺侧基聚谷氨酸链段的三嵌段双亲共聚物。所得共聚物可利用苯硼酸与邻苯二酚的可逆共价结合作用担载苯硼酸修饰的蛋白药物，同时利用三级胺侧基在生理条件下的疏水性质担载化疗药物，实现两种药物的有效共担载。当处于肿瘤细胞内酸性环境时，该共载体系中的苯硼酸与邻苯二酚结合作用解离，同时三级胺侧基质子化变亲水并产生质子海绵效应（导致内涵体/溶酶体逃逸），可实现蛋白药物和化疗药物的共同释放。此外，所释放的苯硼酸修饰的蛋白药物可经细胞内活性氧响应激活，进而实现与化疗药物的协同抗肿瘤效果。